Abdominal aortic aneurysm (AAA) is a common disease and a leading cause of death and morbidity in the elderly. The etiology of infrarenal aortic aneurysms remains obscure although increased proteolysis appears to be fundamental to this process. We have previously identified a transcriptionally-mediated increase in total and processed/active matrix metalloproteinase-2 (MMP-2) in AAA tissue. That MMP-2 is required for AAA has been established by recent experimental work from our group showing that MMP-2 knockout mice are resistant to aneurysm induction. We present exciting new preliminary data showing that MMP-2 mRNA and protein levels are increased in the skin of AAA patients in comparison to patients affected with atherosclerotic occlusive disease (AOD; atherosclerosis without aneurysms) or controls (minimal atherosclerosis, no aneurysm). Plasma MMP-2 levels are also increased in AAA compared to AOD or controls. This latest finding suggests systemic over-expression of MMP-2 and is consistent with the known propensity of AAA patients to get incisional hernias after abdominal surgery. Among the single nucleotide polymorphisms found in the MMP-2 promoter, only one alters MMP-2 protein levels by disrupting an Sp-1 binding site. We I hypothesize that systemic MMP-2 dysregulation leads to aneurysm formation. This proposal will investigate a number of aspects of MMP-2 metabolism by: 1) determining MMP-2 protein levels in the blood of a larger group of AAA, AOD and control patients; 2) determining the frequency of a common, functional polymorphism in the MMP-2 promoter in AAA and AOD patients; 3) determining the ability of short interfering RNA molecules (siRNA) to inhibit MMP-2 expression and prevent aneurysm formation in a murine AAA model; 4) determining the role of macrophage-derived MT1-MMP in the activation of MMP-2. The goal of aim 1 is to develop a screening test for AAA. Aim 2 could identify an important underlying mechanism and explain individual susceptibility to AAA. The siRNA to be tested in aim 3 has great potential as a specific molecular tool for investigation and therapy. The interaction between resident MMP production and local activation by inflammatory cells (specific aim 4) is an Important fundamental question in matrix biology. Answers to the questions addressed by this proposal will greatly advance our current knowledge of AAA and other inflammatory disease processes associated with matrix destruction.